Abstract. Our goal is to create new drug or peptide therapies for chronic GVHD (cGVHD). We developed a new cGVHD model of multi-organ system injury and advanced the field by making the important observation that IgG deposition in tissues causes cGVHD. Germinal centers (GCs) are sites where B cells produce plasma cells (PCs) that secrete immunoglobulin (Ig). Our central hypothesis is that cGVHD results from a vigorous GC reaction, PC secretion of Ig with deposition in cGVHD organs causing collagen fibrosis, and these processes are treatable using clinically available or drugs synthesized in Core E. These include inhibitors of Bruton's tyrosine kinase (BTK), B cell lymphoma-6 (BCL6), and inositol tetrakisphosphatase 3' kinase (ITPKb). Epigenetic modifiers, including a first-in-class bromodomain inhibitor drug, will be used to optimize BCL6 inhibitor efficacy. Given the importance of TFH IL-21 in cGVHD therapy, we selected a Rho-associated kinase 2 (ROCK2) inhibitor that blocks IL-21 production. The ubiquitin-proteasome system regulates cytokine production and antigen-processing; PCs are dependent upon proteasome function for survival. Bortezomib inhibits the constitutive proteasome and the immunoproteasome and we found that nano-encapsulation improves efficacy. Since constitutive proteasomes degrade and process antigens, we will more selectively target the immunoproteasome. cGVHD patients are susceptible to viruses yet have high anti-leukemia effects. We will test our top agents for anti-viral and GVL responses in cGVHD mice, which will guide our development of up to 3 for clinical trials by Pr1. To curtail fibrogenic mechanisms, we will target monocytes/macrophage survival, inhibit the TGFb production and respone, and target the Jak1/2 pathway with a drug used for myelofibrosis. We will build upon our data that lung fibrosis and collagen type V (col V) deposition can be prevented by in vivo tolerization with a collagen V peptide. Aim 1: GC B cells & PCs are critical targets for ameliorating cGVHD. We will test the hypotheses that key transcription factors and signaling pathways critical for GC and PC generation will prevent cGVHD (1A). We will test nanoparticle delivery and selectively targeting the immunoproteasome in PCs (1B). Aim 2. TGFb release by donor & macrophages results in collagen deposition and fibrosis. We will test the hypothesis that Jak1/2-dependent, CSF1R+ macrophages are activated by IgG binding to FcRs, releasing TGFb that induces col V deposition (2A) and that col V induces anti-col V Ab and T cell responses, amenable to col V peptide-induced tolerization (2B). Aim 3. cGVHD therapeutic agents will permit effective anti-viral and GVL responses. We hypothesize that GVL (3A) and anti- viral (3B) responses will be retained with preferred agents from aims 1,2. Pr2 strengths include the importance of new drug therapies for cGVHD, access to unique mice and reagents for clinical trials, a strong medicinal chemistry core, and investigators with outstanding expertise in B cell biology and fibrosis. The P01 has deep synergies: Pr 2 will provide a foundation for analysis of cGVHD patient samples in Pr 3 and clinical trials in Pr1.